Now There are Eleven,but So What?

by Dave Gilden

With the April 7 FDA approval of Pharmacia & Upjohn's delavirdine (brand name: Rescriptor), there are now 11 drugs marketed in the U.S. for suppressing HIV. Delavirdine, like nevirapine (Viramune®) before it, is a nonnucleoside reverse transcriptase inhibitor, or NNRTI. NNRTIs chemically combine with HIV's reverse transcriptase enzyme to block the virus' infection of new cells. Their role in HIV therapy has always been uncertain because HIV rapidly develops resistance when exposed to the current members of the class, at least when these drugs go up against HIV alone: The best bet seems to be as first-line therapy in combination with fresh nucleoside analogs. Then, the protease inhibitors could be saved for occasions when HIV levels are very high or stubbornly resist treatment with other drugs. But then again, maybe it is best to go to maximum suppressive therapy with the less resistance-prone protease inhibitors in the first place.

Reading delavirdine's package insert is a scary experience that will put off most people from trying the compound. In the first place, resistant HIV emerges within a few weeks of taking the drug, due to a single mutation. That mutation most often occurs at reverse transcriptase's amino acid 103. This same mutation also reduces HIV's sensitivity to Du Pont Merck's experimental and much more active NNRTI DMP 266. It would be a shame to lose some of the advantages of DMP 266 through previous use of delavirdine. Largely because of its resistance problem, delavirdine provided no statistically significant benefit in two of the three clinical trials that led to its approval. One of these, ACTG 261, involved participants who had no prior therapy or less than six months of AZT. Preliminary analyses of the viral load and CD4 count data in ACTG 261 indicate that AZT/ddI is virtually equal to AZT/ddI/delavirdine or ddI/delavirdine and decidedly better than AZT/delavirdine. In another study, the AZT/delavirdine combination did do better than AZT alone in a cohort with six months or less of prior AZT therapy. This improvement was not apparent when evaluating CD4 count changes, only in terms of viral load. (A further reduction in HIV levels of only about 0.1 log -- 20% -- after week eight could be attributed to delavirdine. At week four, this difference briefly reached 0.5 logs or 67%.)

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Then there is the problem that delavirdine therapy requires taking four 100 mg pills three times a day. This comparatively large burden, of course, comes in addition to the other antiviral drugs with which delavirdine must be taken (delavirdine monotherapy is strongly advised against). With the recommended regimen, delavirdine blood levels vary considerably from person to person, and on average women achieve 31% higher levels than men. Delavirdine is metabolized by the liver and inhibits the same CYP3A hepatic enzyme that the protease inhibitorritonavir does (though not to the same extent). Like ritonavir, delavirdine comes with a long list of warnings concerning drugs whose blood levels it raises due to this suppression of liver metabolism. Delavirdine also causes skin rashes, usually (but not always) temporary, in about 20% of patients. Finally, it causes birth defects in rats.

This is not a very attractive drug. Except, except... One of the pieces of information that led the FDA to OK delavirdine was some data from Paul Bellman, M.D., a New York City AIDS specialist in private practice. Taking advantage of the preapproval delavirdine expanded access program, Dr. Bellman added the compound to the regimens of 60 of his patients who were experiencing rising viral loads despite being on AZT/3TC/indinavir. (In some patients, the AZT was switched to d4T at the same time). Lo and behold, 15 of the 27 patients whose records have been made available experienced a rapid viral load decline amounting to more than one log (90%) by the second or third month. Dr. Bellman has no way of checking, but he thinks that the people failing the indinavir regimens were not achieving high enough blood levels of this protease inhibitor, possibly due to poor absorption in the digestive tract. Delavirdine conceivably could have raised the patients' average indinavir levels by two-fold or more, due to its effect on the liver, where 80% of indinavir is broken down.

Dr. Bellman observes, "Delavirdine added to nucleoside analogs does not have these benefits. But adding delavirdine, a potent drug, to indinavir makes it potent, too. So now there are two potent new drugs in the patient's antiviral combination."

Dr. Bellman combines delavirdine with the standard indinavir dose of 800 milligrams three times a day. Upjohn, though, recommends that indinavir should be reduced to 600 mg three times a day when co-administered with delavirdine. The worry with high indinavir levels in the body is that some of the compound will end up in the kidneys as an extremely painful precipitate or sediment. Dr. Bellman says he has noticed no increase in this kidney stone problem, which strengthens his feeling that his failing patients had abnormally low indinavir levels to begin with.

The doctor's whole strategy rests on his personal intuition. He has not actually monitored the indinavir levels in any of his patients since such a test is not commercially available. His experience points out a gap in current research -- why people fail treatment regimens is not examined systematically. In particular, the drug levels achieved in patients are rarely looked at.

Merck, which developed indinavir, is now collecting blood samples from people who have not responded well to the compound. The reasons why people fail seem varied, according to Merck researcher John Condra. He says, "We don't have any evidence that failures have low blood levels. This is one possibility. Among the other explanations are drug resistance and inadequate compliance." If the problem is failure to take indinavir on schedule or to take it with food rather than on an empty stomach, this should be corrected first before adding delavirdine. If the problem is indinavir-resistant HIV and not low indinavir levels, the benefits and dangers of adding delavirdine are uncertain.

Adding to the mystery, Dr. Bellman notes that he has seen patients continue to fail when delavirdine was added to their indinavir regimen and then succeed on indinavir plus nevirapine. But nevirapine reduces indinavir levels rather than raising them.

Like the reasons for protease inhibitor failure, protease inhibitor/NNRTI combinations have suffered from lack of attention. Manufacturers in the past have tried to position their NNRTIs as substitutes for the more expensive protease inhibitors in combination regimens with nucleoside analogs. It nonetheless makes more sense to combine NNRTIs with protease inhibitors rather than nucleoside analogs since then two different HIV enzymes and points on the virus lifecycle are attacked rather than just one. In one small Vancouver trial, for people with AIDS who had failed all nucleoside analogs, the combination of 3TC, indinavir and nevirapine was surprisingly successful (see Treatment Issues, February 1997). Also, the two-drug combination of DMP 266 and indinavir in trials has suppressed HIV as effectively as most three drug combinations.

Dr. Bellman's results in his first patients are drawing increasing attention in New York City and elsewhere. The complete results are not in, though. For most of these initial patients, adding delavirdine to indinavir did not drive HIV down to undetectable levels (below 400 HIV RNA copies/ml of plasma). This leads to fears that long-term stability will not be maintained, given HIV's propensity to develop resistance to either of these two compounds when residual viral replication is possible during treatment. The clock may be set back, but usually it is still ticking; successful ways to recover from treatment failure need further elaboration.

Part of that solution appeared to be Upjohn's "spawn of delavirdine," a series of altered delavirdine compounds that the company tested in the lab and found to be active against delavirdine-resistant HIV. These compounds were described in a series of four papers over the past year, but Upjohn now says it has no attention of developing them further because they exhibited poor stability in animal studies. More recently, Upjohn has come up with a new set of NNRTIs, the "pryrimidine thioethers," which also are potent against delavirdine-resistant HIV as well as nonresistant virus. Their absorption and stability reportedly are excellent in rats, but Upjohn is still evaluating their future development. There is considerable speculation in the AIDS community that Upjohn is pulling back from HIV research. It will be interesting to see what the company does.

Ganciclovir Implants:One Year Later

by Jill Cadman

Chiron Vision's Vitrasert eye implant for treating CMV was approved by the FDA in March of 1996 (see Treatment Issues, March 1996). The implant is an important breakthrough because it is able to deliver steady amounts of ganciclovir directly to the retina for months. Besides making massive daily infusions of ganciclovir unnecessary, it increases the drug's effectiveness by bypassing the blood-retina barrier and delivering high levels of ganciclovir to the localized site of CMV retinitis. A year's experience with Vitrasert has better defined its potential for treating CMV.

The Implant and Retinal Detachment

There were initial concerns about safety, especially regarding the risk of retinal detachments. Daniel F. Martin, M.D., in Atlanta, a major figure in the pre-approval implant trials, was among the first to voice these concerns. But CMV disease itself leads to retinal detachments in a large proportion of patients. Cumulative one-year risk ranges from 24% to 50%, according to various reports. Hence, it is not easy to pinpoint the cause of a detachment in an implanted eye.

After having performed the operation on hundreds of patients, Dr. Martin now feels that the problem was somewhat overstated. Although he maintains there is an increased risk in the range of 5% to 10% in the first two months after the implant surgery, he estimates that the one-year risk is about the same as for those patients on systemic treatment. Similarly, Murk-Hein Heinemann, M.D., of Cornell University Medical College, presented a study in May at the Association for Research in Vision and Ophthalmology (ARVO) that found a total 4.8% detachment rate following implantation (abstract 3415-B16). The Cornell study concluded that detachment is an uncommon complication with the implant.

Dr. Martin stated that CMV activity itself is probably the single most important risk factor in retinal detachment, followed by location and extent of disease. "Every time you get a [CMV] reactivation, you get areas of atrophy and small holes can develop in the retina. It makes sense that an implanted eye over time is going to have lower risk because you don't get the multiple reactivations that you do with IV meds."

Joseph Eviatar, M.D., an ophthalmologist in New York City, also voiced early worries about the risk of retinal detachment. He now concurs with Dr. Martin's observation that the rate of detachments appears to be about the same with the implant as with systemic treatment. Dr. Eviatar said that his experiences have been overwhelmingly positive. "Patients have had their CMV controlled for six to eight months with a single implant and have been able to preserve vision. Most patients have a couple of weeks of slight blurring of vision immediately after the surgery, but that usually resolves."

There have been problems in the past obtaining insurance reimbursement for the implants, which cost about $4,000 plus surgery expenses. These seem to have been largely resolved. Anyone having difficulty with reimbursement or lack of insurance coverage may call Chiron Vision's patient assistance program at 800/EYE-IMPL.

Concurrent Systemic Treatment

The implant is able to deliver medication directly to the infected retina, but it does not protect the retina in the other eye or the rest of the body from the spread of CMV. For that reason, most patients are also taking oral ganciclovir as adjunctive therapy. A large, ongoing trial sponsored by Roche (Protocol 2304) compares the implant plus 4.5 grams of oral ganciclovir versus the implant plus oral placebo versus intravenous ganciclovir alone. Results of this trial are expected this summer and will document the value of systemic ganciclovir protection, both in oral and IV formulation.

Documenting the value of systemic protection is critical. Oral, not to mention IV, ganciclovir is a hard drug to take. Therapy requires 12 to 18 pills a day, at a cost of at least $15,000 a year. Many patients on oral, as well as IV, ganciclovir experience bone marrow suppression, evidenced by reduced numbers of white blood cells (29% of patients on the oral formulation) and red blood cells (19%). Intravenous Neupogen (G-CSF) or Epogen (erythropoietin) can counteract the effect on white or red blood cells, respectively. On the other hand, all patients not on systemic medication must be monitored closely so that treatment can begin at the first sign of CMV progression to new tissue.

CMV (cytomegalovirus) is a prevalent virus from the herpes family which can cause opportunistic infections in immune-compromised persons. It is estimated by the Centers for Disease Control (CDC) that one-third of all Americans are infected with CMV. The virus is transmitted through body fluids or transfusions. It is common for infected people to show no symptoms while CMV is inactive. There is a CMV antibody test commercially available for those wishing to know if they are infected. The risk of developing active CMV disease increases in persons with AIDS as CD4 counts decrease. Those with CD4 counts below 100 are at greatest risk and should begin ophthalmologic screenings for CMV retinitis. As CD4 cells drop below 50, screening should become more frequent. Screenings should continue even if CD4 cell counts increase due to antiviral therapy.

CMV is a systemic infection that can cause disease in many parts of the body in addition to the eye, including the brain, colon, esophagus and other organs. The most common manifestation is CMV retinitis, which causes lesions on the retina. Severity depends on the location of the lesion. Zone 1 disease causes damage in the highly sensitive central retina (the macula) and is most sight-threatening. Zone 2 includes the periphery of the retina. Infection there is less dangerous to vision, although it may spread to the central retina. CMV retinitis is frequently associated with CMV encephalitis, a severe brain disorder with multiple neurological complications (see Treatment Issues November 1996).

Treatment for CMV retinitis is given in two phases. An initial induction therapy consists of twice a day intravenous ganciclovir or foscarnet (or once weekly cidofovir) administered for two to three weeks. The purpose of induction therapy is to halt disease progression and prevent blindness. Induction is followed by maintenance therapy which consists of daily ganciclovir or foscarnet infusions, biweekly cidofovor infusions, or other treatments (see article) to prevent or delay reactivation of viral replication. It is difficult to completely suppress CMV, and if there is a reactivation, the patient will need "reinduction" via intravenous infusions.

Systemic medication can also be used as prophylaxis for persons with low CD4 counts who have never developed active CMV disease. There are indications that the choice of such therapy depends on a patient's CMV viral load. Those with very high plasma CMV burdens (over 50,000) may require preemptive intravenous (high dose) therapy, even when there is no evidence of active disease, while those with low CMV viral loads (below 50,000) may receive satisfactory results from a course of daily oral ganciclovir. (See Treatment Issues , September 1996).

Retinal detachment is a frequent complication of CMV infection. It occurs when a hole in the retina allows ocular fluid to seep behind, causing the retina to separate from the back of the eye (the choroid). The first symptom is often the appearance of small moving spots known as floaters. Surgery may be necessary to repair the hole and reattach the retina. The injection of silicone oil may also be used in the treatment of retinal detachments. Whatever the treatment, some loss of visual acuity can result. -- JC

Replacing Vitrasert: Immediate or Deferred?

The Vitrasert implant, which effectively prevents progression of CMV retinitis as long as it releases adequate amounts of drug, requires replacement every five to eight months. Inserting the implant is performed under local anesthesia, and patients can go home the same day. The whole procedure takes 30 to 45 minutes. Nonetheless, replacement is serious surgery and carries with it various risks, such as the retinal detachments noted above and temporarily clouded vision. But waiting for CMV reactivation before replacing the implant risks further damage to the retinal tissue. This damage may lead to permanent loss of visual acuity or function.

With the advent of highly active antiretroviral therapy (HAART), some doctors hoped that improvements in CD4 counts would translate into lower risk for reactivation of CMV disease, calling into question the need for pre-planned implant replacement. However, increasing a patient's CD4 count through HAART does not always prevent CMV reactivation. Dr. Martin stated, "I stopped doing scheduled exchanges for awhile and was disappointed. I had some patients with very high CD4 counts and their CMV reactivated at about the same time I would have expected."

Dr. Martin advises those who have Zone 1 (central) disease to have scheduled replacements because they cannot afford to take a chance on loss of vision. For those with Zone 2 (peripheral) disease, Dr. Eviatar stated, "If the patient is doing better systemically and the lesion is not site-threatening, I think it's reasonable to wait and see how they respond. It may be that with the protease inhibitors, they are better able to control the CMV on their own or with oral ganciclovir."

The Effect of Anti-HIV Treatment on CMV

A letter published in the May 21 issue of the Journal of the American Medical Association (JAMA) describes four patients on HAART (including nucleoside analogs and protease inhibitors) who were able to control CMV retinitis without using any specific anti-CMV medication. After initiating HAART, all of the patients' CD4 cell counts increased to over 200. Three patients discontinued treatment with either oral or IV ganciclovir and the CMV retinitis remained inactive, so far for four, five and seven months. The fourth patient refused any CMV treatment and his active retinitis spontaneously resolved and remained inactive for more than 12 months.

Caution should be used when interpreting this small number of case reports. The first author of the letter and clinical director of the National Eye Institute, Scott Whitcup, M.D., stated, "We will need more information before recommending that all people with CMV retinitis and elevated CD4 counts stop their anti-CMV medications." Dr. Whitcup would not recommend coming off anti-CMV medication outside of a carefully picked patient population with extremely close supervision.

Mark Jacobson, M.D., and colleagues at the University of California San Francisco presented a study at the Fourth Conference on Retroviruses and Opportunistic Infections (abstract 353) representing the other end of the spectrum. The Jacobson study looked at five patients who had CMV retinitis diagnosed despite a CD4 count of 200 or more. Four to 24 weeks before the diagnosis, all patients had CD4 counts below 85, and four to eight weeks before the CMV diagnosis, all patients had initiated HAART. The researchers then examined data from 76 consecutive patients enrolled in a treatment trial for CMV retinitis. During the period from July, 1995 through February, 1996, only one patient out of 27 had CD4 counts above 50 and zero out of 27 patients had CD4 counts above 100. From March, 1996 (when HAART became widely available) through August, 1996, 14 out of 49 patients had CD4 counts above 50 and seven out of 49 had CD4 counts above 100. The investigators concluded that the immunological benefits of HAART may not fully protect against CMV retinitis, which may occur more commonly now in patients with CD4 counts above 50.

The authors of the JAMA letter suggest that such cases of CMV may be due to subclinical (asymptomatic) CMV retinitis existing prior to the onset of HAART. Dr. Whitcup notes that retinitis developed in patients in the Jacobson study shortly after initiation of HAART and feels that CMV would have eventually emerged in these patients in any case. Dr. Whitcup has seen his own patients develop such symptoms of CMV retinitis as vitreous floaters shortly after starting on HAART. It is possible that HAART cannot immediately protect a patient who already has a subclinical case of retinitis, but it may be protective against CMV progression over the longer run no matter what the initial status of the disease.

Dr. Whitcup said, "I have yet to see someone develop CMV retinitis who has been on HAART for over three months and whose CD4 counts are over 50 -- although I think there may be cases out there where that occurs." Of course those who have been on combination therapy for extended periods may experience "HAART failure" and subsequent CD4 count declines. Once CD4 counts fall below 50, there will be renewed risk for CMV progression.

The National Eye Institute is seeking to recruit AIDS patients with non sight-theatening CMV retinitis for further study at the NIH. A small 12-person trial will attempt to provide further insight into when it is appropriate to discontinue CMV treatment in patients on HAART. Anyone interested in this trial should contact Cheryl Perry at 301/435-4559.

Improvements in the Pipeline

As people survive longer with AIDS, eight-month implants appear more insufficient than ever. Chiron Vision is now developing a second generation implant called Vitrasert II that will release ganciclovir for a minimum of 18 months and possibly last as long as 24. Chiron hopes to start pilot human studies (phase I) by the end of the year.

There also is room for improvement in oral ganciclovir for maintenance therapy to prevent CMV reactivation. The current standard three-gram dose is not as effective as IV ganciclovir. Raising the daily dose of oral ganciclovir to 4.5 grams works better (see Treatment Issues, September 1996), but requires even more pills and expense. Roche's ganciclovir prodrug (RS-79070) is much more absorbable in the gut than the present version of ganciclovir and breaks down into the active form once in the body. The prodrug's oral bioavailability is about 61%, compared to about 8% for the current oral formulation. Data presented by Roche this past winter at the Fourth Conference on Retroviruses and Opportunistic Infections (abstract LB19) demonstrated that the same levels of serum ganciclovir can be achieved with the prodrug as with IV ganciclovir.

Providing that the pharmaceutical companies move forward, the future standard of care might employ Vitrasert II to treat the local manifestation of CMV retinitis for two years and one pill of ganciclovir prodrug per day to control extra-ocular disease. This treatment strategy would avoid what Dr. Martin calls "the emotional roller coaster of going back and forth from induction to maintenance therapy," which is the current experience of most people with CMV retinitis.

As this article was being readied for press, Hoffmann-La Roche announced that it was deferring development of the ganciclovir prodrug -- see box.

The current oral and intravenous formulations of ganciclovir call for arduous dosing regimens. Long-term treatment with these compounds is difficult and compliance can be problematic. Improved versions of ganciclovir are imperative. Roche's ganciclovir prodrug (RS 79070) would represent a significant improvement, requiring only one to two pills per day to achieve therapeutic levels of ganciclovir in the body.

Roche had planned three clinical trials for the prodrug: one for treatment, one for prevention and one for induction therapy. Two of those three trials are now on hold. According to a company letter sent to investigators, "A decision has been taken within Roche to reassess the development of the ganciclovir prodrug. This action has been precipitated by an apparent decrease in the incidence of new CMV disease which may be attributed to the wide availability of highly active antiretroviral therapies (HAART)."

The induction trial (Protocol WV 15376B) is currently the only one to go forward. About 20 sites across the country are now seeking to enroll a total of 70 participants. The trial will compare three weeks of intravenous ganciclovir induction therapy (two two-hour infusions a day) and one week of IV ganciclovir maintenance therapy (one two-hour infusion a day) with three weeks of prodrug induction therapy (two pills a day) and one week of prodrug maintenance therapy (one pill a day). After four weeks all participants will receive the prodrug.

Slow enrollment in this trial was another factor in Roche's decision to hold off on the other two studies. The induction trial is due to be fully enrolled by the end of July, but not all sites were ready to enroll participants until April. Quick enrollment now may cause Roche to reconsider its position. Anyone interested in participating should call 800/TRIALS-A for more information.

The induction trial is too small to be decisive in the FDA approval process. Unless Roche makes a stronger commitment to the development of the prodrug, approval will be delayed indefinitely, and the drug will not reach the market any time soon.

Aside from being unconscionable, the decision to delay the prodrug's development is based on little hard information and runs counter to prevailing medical opinion. Although HAART may delay CMV emergence by slowing AIDS progression, most experts fear that this is only a temporary reprieve. Some clinicians feel that CMV incidence is already rebounding. As people with AIDS are living longer, the occasion to administer CMV medications for prophylaxis, induction or maintenance and the length of time on such medications may well increase.

Therapies that are easy to administer are vital to successful management of AIDS and HIV infection The dosing requirements of the current oral and intravenous formulations of ganciclovir make them unsuitable for extended use. The prodrug would improve the quality of life of many people. Roche needs to look beyond its own short-term profit margins to the larger picture. --JC

Happiness Reigns in the Drug Marketplace

by Karen Kuller

A new trend is changing the face of AIDS. Increasingly, information on HIV treatment options is gaining exposure through drug companies' marketing tactics -- specifically, mass-advertising. A two-page ad in this month's issue of GQ depicts a mountain-climber who struggles to make his way up a rocky cliff, and ends up on top. The ad, which also appears in Esquire and Details magazines, is for Merck's protease inhibitor, Crixivan. Initially distributed exclusively through the Pittsburgh-based Stadtlanders Pharmacy, Crixivan will be sold at more than 25,000 pharmacies nationwide starting in May.

Once lured to court AIDS and gay community groups because of their wide consumer reach, drug companies are resorting to more traditional methods of direct-consumer marketing as competition among the protease inhibitors heats up. The market's dominant player, Merck, has felt this pressure the most.

Its newest and fiercest rival, Agouron, launched an aggressive campaign to publicize Viracept's low toxicity and ease of use upon its approval in March. Only one month later Viracept represented 23% of new protease inhibitor prescriptions, according to one analyst report.

With an estimated 10,000 new prescriptions being filled each month, drug companies are becoming more and more anxious to get the message out that theirs is the superior product by whatever argument they can advance. The irony is that the messages conveyed about HIV through the media continue to reduce the disease to mere imagery, even as treating it grows more medically complex. Such imagery includes the notion of a war being waged in the blood where billions of T-cells are destroyed every day, says Joseph Sonnabend, M.D., and that "now we have drugs that can stop it all." In Merck's ad, phrases like "battle against HIV" and the tagline "focus on the rest of your life" are typical of ideas feeding the popular perception that AIDS is a manageable, even curable disease. Roche's tagline "consider a protease inhibitor you can live with," which accompanies pictures of happy, smiling people, strikes a particularly ironic chord: though perhaps tolerable, the product in its present formulation and dose does little to reduce viral load.

All ads include the highly technical patient package insert as required by the FDA. The duality of advertisements, where self-promotional imagery juxtaposes objective information, is reflective of the larger issue that is at stake with this approach to disseminating information on the treatment options available to people with AIDS. "Maybe these companies are reaching people who aren't getting this information elsewhere, and maybe they're giving them very useful treatment information," says Spencer Cox of the Treatment Action Group, "On the other hand, these people may be getting information that is not accurate or which they can't evaluate within the appropriate informational context."

Indeed, if raising awareness about HIV and combination therapy among the public-at-large can be construed as one advantage of mass-advertising, then the consequences of increased brand-name recognition should be construed as a disadvantage. Given the highly complicated regimens that characterize triple-combination therapy, using potent imagery and slogans to describe a protease inhibitor can seem oddly inappropriate. "This is not Rogaine or an antihistamine," says Jeanne Bergman, a policy analyst at Housing Works, "I find it peculiar to see ads for such heavy, heavy drugs."

With this comes the fact that combination therapy is still a matter of choice best addressed through active dialogue between a patient and his or her physician. Brand-name recognition should carry no clout in a decision-making process that involves individual considerations for physician and patient alike, including patient history and ease of use. As Spencer Cox put it, "I'm not sure that engendering consumer confidence is the most effective way to ensure the best healthcare." Rather, says Mark Snyder, M.D., an infectious disease specialist with the Mid-Atlantic Permanente Medical Group in Washington, D.C., the advertising can do more harm than good by "creating the belief that one drug is superior to the others when, in fact, it is not."

But creating that impression seems to be what the pharmaceutical industry is focusing more of its efforts on doing. With analysts predicting that the protease inhibitor market will exceed $2 billion by 1999, protease inhibitors are becoming a promising commercial enterprise indeed (Alex Brown Report, April 29, 1997). Concerns about cross-resistance are further supporting the ambitions of companies like Merck, Abbott, Roche, and Agouron to make their protease inhibitor first in line for inclusion in triple combination therapy. Drug resistance is a completely unsettled field that lends itself to widely different spins by the various protease inhibitor manufacturers.

The AIDS community has been insisting that drug companies proactively communicate information about their products since the beginning of the epidemic. "PWAs revolutionized the way medicine is practiced in our country," says Joy Schmitt of Agouron, "They are our most educated consumers, and the industry has responded to that." Yet information about just how these new drugs will affect the future of people with AIDS or HIV remains scarce. HIV therapy has come a long way since the introduction of AZT and ddI. Today, the only thing that is definite about HIV treatment is the dissenting medical opinion on when to initiate therapy, and the plethora of possible combination protocols. Observes Harold Grossman, M.D., "The truth is always somewhere between what all the companies tell you."

As Abbott, Agouron, Merck and Roche ponder their response to each other's latest ads, the bottom line is that clinical data remain the sole basis for judging the value of their products. Generating solid, clear information on potency and durability of effect is the best marketing technique there could be, whether that information is communicated through patient education material, community groups -- or ads.

It's banned -- no, it's just warned -- wait a minute, the crisis is over. This spring was a controversial one for SPV-30, an extract of the European boxwood tree made by the French company Arkopharma. SPV-30, which reputedly has anti-HIV properties, is sold here by some AIDS buyers clubs and a few pharmacies. For a time it also was available in America through a large "informal" trial protocol.

On March 5, the FDA's New York office sent a warning letter to The Health Connection, SPV-30's Long Island-based U.S. distributor. The letter stated that because of specific disease claims made in the product's labeling (which the FDA defines to include advertising and promotional literature), SPV-30 is now considered a drug rather than a dietary supplement. It cannot be distributed without an FDA-approved New Drug Application, the letter said.

On the advice of its lawyer, The Health Connection then suspended all sales of SPV-30 until the matter was cleared up. This decision triggered assertions that "the U.S. Food and Drug Administration has shut down the distribution of SPV-30," as stated in a nationally circulated letter from two AIDS buyers clubs (the Boston Buyer's Club and Direct AIDS Alternative Information Resources in New York). Although the media were quick to repeat this statement, FDA spokesperson Richard Kline observed, "The labeling is the problem. It talks about CD4 cells and viral load. All the company has to do is to change the labeling and make it a dietary supplement... The FDA did not block sales, though everybody said it did."

Ben Cohen, head of The Health Connection, says that his offer to revise his company's literature was initially rebuffed by the FDA. In any event, an April 21 meeting between Ben Cohen, buyers club representatives and FDA officials, resulted in the FDA promising not to further hinder distribution of SPV-30 if The Health Connection refrains from making specific medical claims.

"It was clear from the beginning that they [the FDA representatives] were scolding the New York office for being so quick to react, without consulting the community. They apologized," said David Stokes, director of the Boston Buyer's Club, which with other buyers clubs can continue to distribute literature about SPV-30 with little restriction.

Still, it is in the public interest not to overplay the available data. Last year's increasingly bold SPV-30 ads made poorly supported claims. David Stokes, who organized the "informal" trial in which people received free SPV-30 in exchange for their lab test results, likewise has made many public presentations lauding the "encouraging" data. Yet his study recorded no appreciable changes in the 400 participants' blood work. CD4 counts dropped slightly on average over six months, and HIV levels were virtually unchanged among the 84 people who sent in viral load data.

Release of the results from a blinded, controlled French trial is expected this summer. This 18-month trial enrolled 145 people with CD4 counts between 250 and 500. If objectively and disinterestedly analyzed, its data will provide a more definitive word on SPV-30's activity. -- DG

Roche Brings New Formulationof Saquinavir To FDA

by Jill Cadman

On May 12, Hoffmann-La Roche announced that it was applying to the FDA for approval of the long awaited "soft gelatin capsule" formulation of saquinavir. The soft gel capsule contains the protease inhibitor saquinavir blended with a proprietary lipid mixture that raises intestinal absorption of the compound to 12% of the total drug available, three times the abysmally low 4% observed with the hard capsule.

The recommended dose of the new version is 1,200 mg three times a day (TID), compared to 600 mg TID for the hard capsules. Taking this much will require 18 saquinavir soft gel capsules per day and provide eight to ten times the drug exposure of the current formulation. The eight-week dose-ranging study (NV15107) that identified 1,200 mg TID as the preferred dose recorded a respectable, though hardly record-breaking, 1.43 log (96.3%) drop in viral load among 22 volunteers on saquinavir monotherapy.

The safety study (NV15182) showed few adverse side effects with the new formulation, but caution should be advised for those with a history of liver disease. In addition to the safety data, the FDA has recently requested a head-to-head activity study comparing the two formulations to prove that the soft gel is an enhancement over the hard capsule. Sixteen-week activity data from this study (NV15355) should be available by mid-summer and will be submitted to the FDA during the review process. Roche expects to receive the FDA's go-ahead to market the improved saquinavir by the end of this year.

Community activists have raised concerns about the continuation of Roche's aggressive marketing campaign which is advertising saquinavir as "a protease inhibitor you can live with." The hard capsules are administered at 600 mg TID, a suboptimal dose that may breed resistance to both the new formulation and other protease inhibitors by failing to have much impact on HIV replication. At a community meeting in May, activists asked Roche to pull the campaign until the soft gel capsules are available. Tammy Lewis, Product Director for saquinavir, conceded that the best way to use the current formulation is in combination with the protease inhibitor ritonavir, which raises blood levels of saquinavir ten-fold by blocking the drug's metabolism in the liver. But the saquinavir/ritonavir combination has not been reviewed, much less approved, by the FDA, and Roche is prohibited from promoting it.

Roche is now pursuing approval of an expanded indication of saquinavir for use in combination with other protease inhibitors. Approval is not likely within the next 12 months and would probably be limited to specific drug combinations initially (in particular, 400 mg saquinavir plus 400 mg ritonavir), rather than a broad saquinavir/other protease inhibitor indication. Discussions have already taken place between Roche, Abbott and the FDA regarding registration trials in Europe for saquinavir/ritonavir.

Another long-standing community complaint is the current price of saquinavir. At $5800 per year wholesale, the hard capsule saquinavir is at least as expensive as the other protease inhibitors even if it is the weakest. Ms. Lewis says it is "premature" to comment on the pricing of the soft gel capsule. Especially at the preferred 1,200 mg TID dose, the soft gel could prove much more costly than the present version.

No Attrition in Researchon Wasting Therapies

by Dave Gilden

One of the most prevalent and dangerous conditions in AIDS and HIV disease has been chronic wasting, in which people progressively become so depleted of lean tissue and protein stores that their bodies can no longer perform basic functions. In this new era of highly active antiretroviral therapy (HAART), is it still a major concern? Kathleen Mulligan, M.D., who has studied AIDS wasting extensively at San Francisco General Hospital answers in the affirmative: "There're lots of anecdotes -- people proclaiming the end of wasting syndrome," she says, "but I'm not knocked out by what I see here. I don't think we're out of business."

It may be that once the conditions for wasting exist, the syndrome persists even when HIV levels decline. Several small surveys presented at April's Nutrition and HIV Infection conference in Cannes, France found that about a fifth to a quarter of those on aggressive antiviral therapies continue to lose weight or lean body mass. One of the studies observed that there was little correlation between viral load response to therapy and changes in weight. Serono Laboratories has made similar findings in an ongoing survey it is conducting. And the initial results from a study at Tufts University indicate that over the first seven to nine months on HAART, patients gain significant amounts of weight as they eat more, but it is all fat. (presented by Sherwood Gorbach, M.D., at the NIH Conference on AIDS Wasting Syndrome, May 20-21, 1997).

An inability to restore lean body mass (muscle in particular) after acute or chronic weight loss has been the hallmark of wasting syndrome. That inability remains even when a person recovers from an opportunistic infection that triggered the weight loss episode. Another on-going study at Tufts University is observing that, at least in people with high HIV levels, even strenuous exercise programs do not improve body composition. Trial participants did increase their weight by an average 3.8% after eight weeks, but the percent increase in fat and lean tended to be the same (presented by Ronenn Roubenoff, M.D., at the NIH Conference on AIDS Wasting Syndrome, May 20-21, 1997).

(A more definitive word on recovery after successfully suppressing viral load may come from the weight gain substudy that is part of the recently concluded ACTG 320, a trial of AZT (or d4T) plus 3TC with or without indinavir. The substudy will try to determine whether adding the protease inhibitor and obtaining greater reductions in viral load result in greater increases in lean body mass, and whether increased lean body mass is associated with changes in appetite and the body's pro-inflammatory agents (such as TNFa, see below). Until now, drug companies have either not collected or refused to release much information on weight changes in their protease inhibitor trials.)

Growth Hormone Hits the Market

It seems that in addition to potent antiviral therapy, an anabolic (muscle-enhancing) or anti-inflammatory agent may be necessary to reset the body's chemistry after chronic HIV plays havoc with it. Developments in this area continue to make news. December 2 marked the introduction of Serono's brand of human growth hormone (Serostim), which was granted accelerated approved for treating AIDS wasting system in August after a rough ride through the FDA. (For the details of the FDA's critique of Serostim, see Treatment Issues, March, 1996 and August, 1996.)

One of the oddest things about the Serostim approval is that the duration of therapy and a precise definition of what population will benefit remain elusive. Controlled trials of growth hormone lasted only 12 weeks. Average weight gain in these trials was about 2.5 pounds. In the most exhaustive trial, a 178-person affair that included body composition analysis, the weight gain was found to consist of an average lean body mass increase of 6.8 pounds and a 4.3 pound loss in body fat. But, 22% of the participants dropped out or were noncompliant, and of the rest, 26% of those on growth hormone continued to lose weight. Participants in the open-label continuation phases of the trials maintained their weight gains while on growth hormone, but it was difficult to say what would have happened had they stopped. There were many trial dropouts here too, and these people may or may not have resumed their weight loss.

The FDA-approved package insert that comes with Serostim limits itself to recommending that treatment be initiated when a patient's unintentional weight loss reaches 10% of normal body weight. If weight loss continues after two weeks of treatment, the patient's condition should be reevaluated. The insert notes that any acute opportunistic infection may need to be cured, or at least suppressed, before restoration of weight or body composition is possible.

Serostim, injected subcutaneously once a day, is hideously expensive, costing $210 or $252 retail for a daily dose of five or six milligrams. Serono has established a yearly price cap of $36,000 for those who must keep taking Serostim indefinitely to prevent a recurrence of loss in weight and lean body mass. A patient assistance program will also provide free drug to a limited number of people with restricted financial means. For more information on Serostim distribution and financial assistance call the "Serostim Access Line," 800/714-2437.

The enormous expense is not the only reason to use Serostim judiciously. The doses of growth hormone administered for AIDS wasting syndrome (about 0.1 mg/kg of body weight) are very high compared to what is used for other conditions. In the brief AIDS wasting trials, rates of muscle pain (53.7% of those on growth hormone), tissue swelling and stiffness (27.3%), and carpal tunnel syndrome (relatively infrequent) were markedly elevated.

Much of the confusion around growth hormone stems from the fact that AIDS wasting is really a collection of syndromes. The variety of factors at work range from lack of appetite to malabsorption in the gut to metabolic derangement triggered by generalized inflammation, and the precise mix differs from individual to individual. Many of these factors must be treated in tandem. Growth hormone cannot work without sufficient nutrient intake, for example.

The confusion concerning Serostim's therapeutic role may be resolved by an FDA-imposed post-marketing trial. That trial will enroll over 700 volunteers to check on changes in lean body mass, body weight, physical function and quality of life after 12 to 48 weeks on therapy. A series of changes in study design have caused this study to be postponed several times, unfortunately. Some of the existing uncertainties in the protocol may be cleared up by an FDA conference on evaluating wasting syndrome described at the end of this article.

Testosterone Replacement Therapy

Since wasting is multifactorial in origin, then treatment probably should be individually tailored, acting on whatever suitable targets present themselves. There may be many therapies that are more appropriate for wasting than growth hormone in individual cases. For one thing, wasting has frequently been found to be associated with low sex hormone levels (hypogonadism), particularly low testosterone. Steven Grinspoon, M.D., has found that half the men with AIDS-related weight loss have low free testosterone levels (see Journal of Clinical Endocrinology and Metabolism, Nov. 1996; 81(11):4051-8). Parallel findings have been reported for women with HIV, even though women's normal testosterone levels are ten-fold lower than those of men (see Ellen Engelson et al., Eleventh International Conference on AIDS, abstract Tu.B.2382).

Testosterone has a strong stimulating effect on muscle tissue, and replacing lost testosterone might help reverse the attrition of lean body mass. In fact, the Alza Corporation has been implying that its testosterone skin patch (brand name: Testoderm) is useful for AIDS wasting since it was approved last year as testosterone replacement therapy for those with low levels of the hormone. Results from two trials for men and one open-label follow-up are now in, and they show no benefit for the Alza patch as far as weight and body composition are concerned. The patch did substantially increase the male volunteers' testosterone levels, which may have other benefits in terms of libido and overall energy. Alza officials and outside researchers are interpreting these results to mean that testosterone levels were not raised sufficiently to have a detectable anti-wasting effect.

Judith Rabkin, Ph.D., of the New York Psychiatric Institute, argues, "With injectable testosterone, you get a bigger bang for your buck. The patches are hard to stick, so delivery may be a problem. Also compliance could be an issue -- you have to stick a new Alza patch on your scrotum each day." Dr. Rabkin's trial of injectable testosterone is now being written up. Also, Dr. Steven Grinspoon's group at Massachusetts General Hospital (Boston) should soon finish analyzing a trial of intramuscularly injected testosterone in 50 men with AIDS wasting syndrome. Like the Alza trials, this is a six-month testosterone replacement study -- it seeks to restore testosterone to normal in those with low untreated levels. Dr. Grinspoon comments, "Our study will definitively answer the question" of whether mere testosterone replacement is sufficient to reverse AIDS-related weight loss. Finally, the University of Southern California is nearing completion of a trial that specifically compares the Alza patch to injected testosterone.

A competing testosterone patch can be placed on any part of the body, not just the scrotum. It was developed by the TheraTech Corporation and is marketed by SmithKline Beecham under the brand name Androderm. A Los Angeles trial with this patch in men with intermediate HIV infection recently ended. Of special interest, TheraTech has developed a skin patch geared specifically to replace the small amounts of testosterone normally produced by women. A trial of the women's patch is taking place at Massachusetts General Hospital in Boston, and results should be available this summer.

The Grinspoon paper cited above also presented findings that men with AIDS-related wasting actually had higher than normal levels of natural growth hormone, but their bodies did not seem to be responding to it. (In particular, there were insufficient levels of insulin-like growth factor 1 (IGF-1), which is produced by liver cells in response to growth hormone.) "Our data support the case for using very high levels of growth hormone," says Dr. Grinspoon. The recommended dose for Serostim is indeed very high, and the cost is a certain number of generally tolerable side effects. With testosterone, safety may be more of an issue, in part because of its masculinizing side effects. Possible adverse events include acne, increased irritability and, over time, cardiovascular and prostate problems.

A recent paper, however, found achieving supernormal testosterone levels was safe over the short-term as well as highly effective in stimulating muscle development among HIV-negative volunteers (see Shalender Bhasin et al., New England Journal of Medicine, July 4, 1996; 335(1):1-7,52). The New England Journal paper found that adding weight training to testosterone was even more effective.

Dr. Bhasin, who is from Charles R. Drew University in Los Angeles, argues that testosterone might be preferable to growth hormone. Testosterone acts to raise IGF-1 locally, within muscle tissue, whereas the IGF-1 produced by the liver in response to growth hormone spreads throughout the body. He is currently investigating the use of testosterone with and without resistance weight training in men with HIV-associated weight loss, but the testosterone dose administered, 100 mg/week, is only one-sixth that used in the HIV-negative trial. Dr. Bhasin estimates that the cost of testosterone therapy could amount to a mere $150 per year.

Aside from adding exercise to testosterone, Dr. Grinspoon and others are considering combining human growth hormone and testosterone. Other possible combinations include the use of testosterone plus Megace, an appetite stimulant that on its own tends to increase fat stores, with little effect on lean tissue. Megace is a derivative of the female hormone progesterone and actually suppresses testosterone production. ACTG trial 313 is testing whether testosterone replacement in both men (200 mg every two weeks) and women (100 mg every two weeks) can overcome Megace's drawbacks. And in New York, Dr. Rabkin is testing testosterone therapy along with a high amino acid nutritional supplement.

Exploring Anabolic Steroids

An alternative approach is to employ one of the synthetic anabolic steroids that mimic testosterone's muscle-building effects while minimizing its virilizing aspects. In theory, higher doses could be used with little concern for safety. This theory remains to proved, however, and the exact extent of anabolic steroids' muscle-building capacity needs further rigorous exploration.

The most tested anabolic steroid so far has been oxandrolone, which is produced by Bio-Technology General under the brand name Oxandrin. Oxandrolone is an oral drug approved by the FDA in 1962 as a general remedy for weight loss in a variety of conditions including chronic infection. The agent is now being touted in advertisements that strongly imply its efficacy for AIDS wasting syndrome. Oxandrolone's usefulness in AIDS has yet to be established, and an early trial utilizing a 5 mg/day dose found that oxandrolone had no appreciable benefit in AIDS.

Recent trial data suggest that higher doses will be more effective, though. In a paper published last December describing a trial in AIDS wasting syndrome, administration of 15 mg of oxandrolone per day resulted in statistically significant weight gain over those taking placebo through 14 weeks. At week 16, however, this difference (a gain of 1.32 pounds versus a loss of 2.42 pounds in the placebo group) failed to reach statistical significance. Body composition was not measured in this trial. Two studies of oxandrolone were reported last winter at the Fourth Conference on Retroviruses and Opportunistic Infections, and both looked at the effect of oxandrolone at 20 mg a day on body composition (see abstracts 692 and 695). The initial results of each of these studies (after an average of about a month) found about a 6.6 pound increase in weight. Body cell mass (a measure of increased protein stores) averaged 2.6 and 3.3 pounds higher in the two studies. Both these small, open-label trials are continuing, with further improvements noted in the trial participants who have already been on treatment for more than a month.

Two major ongoing oxandrolone trials are following a blinded, placebo-controlled protocol with higher doses. One study is trying 20, 40 and 80 mg per day in men with AIDS-related weight loss. Another is administering 20 and 40 mg per day to women. These trials will enroll about 300 men and 200 women, observing them for 12 weeks to compare oxandrolone versus placebo. In a second 12-week period, everyone will receive active treatment.

At 20 mg/day, it would cost more than $12,000 for a year's supply of oxandrolone at today's prices. A definitely cheaper substitute is the injectable anabolic steroid nandrolone decanoate. Nandrolone is made by Organon Teknica under the brand name Deca Durabolin, and there are also several generic versions. On a per milligram basis, nandrolone costs a sixth to a twelfth of what oxandrolone costs. Unfortunately, no one is pursuing a development strategy for nandrolone the way Bio-Technology General is for oxandrolone.

Some data are available, though. At the Eleventh International Conference on AIDS, Gary Bucher, M.D., and colleagues at the Center for Special Immunology in Chicago described gains in weight and fat-free mass in HIV-positive male volunteers receiving 100 mg/week of nandrolone for 12 weeks (abstract Mo.B.423). These volunteers had not necessarily experienced previous weight loss, however. In another report (see AIDS, June 1996, 10(7):745-52), a group from Sydney, Australia noted gains averaging 8.8 pounds over 16 weeks in 24 men who did have HIV-associated wasting. These men had not gained weight when enrolled in a program consisting of resistance exercise and dietary counseling. (Note that these 24 were from a cohort of 220 men, of whom the rest did succeed in gaining weight from the exercise and dietary counseling alone). The volunteers received 100 mg of nandrolone injected every other week in four months on/one month off cycles. The investigators estimated that the total yearly cost for such treatment would be just $600. A new San Francisco study of nandrolone using 100 or 200 mg/wk has found equivalent results -- a gain of 8.8 pounds at 12 weeks, of which two-thirds was ascribed to increased body cell mass (presented by Marc Hellerstein, M.D., at the NIH Conference on AIDS Wasting Syndrome, May 20-21, 1997).

Summing up his experience with nandrolone, Dr. Bucher said, "The anabolic effect seems equal to growth hormone, but there may be fewer side effects with deca [nandrolone] in terms of joint pain and tissue swelling." The AIDS Clinical Trials Group is at present sponsoring a small trial of nandrolone in women with greater than 5% HIV-associated weight loss. The women will receive 100 mg of nandrolone or placebo every other week for 12 weeks and then everyone will receive nandrolone for another 12 weeks. A second study at the University of Southern California is testing nandrolone with and without resistance weight exercise in men with HIV-associated weight loss. In this trial, the high dose of 600 mg/week will be administered. A third trial is being sponsored by the American Foundation for AIDS research for both men and women with moderate weight loss. This 120-person, 16-week trial will test biweekly nandrolone doses of 200 and 400 mg in men and 100 and 200 mg in women.

Thalidomide: New Results

All these therapies aim at overwhelming the signs of wasting with large amounts of protein-building agents. Rather than reversing the obvious wasting effects, why not aim for the underlying cause? Attempts have been made to do this with thalidomide, which blocks production of tumor necrosis factor alpha. TNFa is prominent among the several immune system's inflammatory agents that have been blamed for the depletion of protein stores during HIV infection. In January, a thalidomide developer, Celgene, of Warren, New Jersey, announced that the data from its trial in 99 people with AIDS wasting showed a statistically significant weight gain. The company seems to have "jumped the gun," as one person close to the trial put it. No data were yet available from the trial to justify Celgene's press release.

In April, a preliminary analysis of this trial was unveiled at a conference on TNFa blockers in Santa Fe. Commenting on the state of data, the study's principal investigator, Morris Schambelan, M.D., of San Francisco General Hospital, said, "The primary efficacy data are pretty solid, but the rest needs careful scrutiny." The results are a little curious in that the higher dose had less effect than the lower one: During the first eight weeks, participants gained on average 4.5 pounds (3.3% of their mean weight) on 100 mg/day of thalidomide, compared 2.2 pounds (1.2%) on 200 mg/day and 0.7 pounds (0.5%) on placebo. Participants continued to gain weight in the eight-week continuation phase. Dr. Schambelan estimates that about half the total weight gained was in lean body mass, although the complete body composition analysis has not been done.

One surprise is that HIV viral load went up slightly (an average of 0.3 logs, or two-fold) in the course of the trial. Reducing TNFa levels should have slowed HIV replication by lessening CD4 cell activation. But then, does thalidomide really reduce TNFa? TNFa levels are still to be assessed in this trial, but Dr. Schambelan noted that in a newly released study of thalidomide in oral aphthous ulcer treatment, the level of both TNFa and its cellular receptors rose somewhat. Thalidomide also failed to reduce IL-2 induced increases in TNFa levels or relieve side effects reputedly associated with the TNFa increases during a trial of IL-2 plus thalidomide (reported at the Fourth Conference on Retroviruses and Opportunistic Infections, abstract 36).

It may be that total TNFa is hard to quantify because blood levels are not necessarily indicative of cells' exposure to the substance in lymph tissue or that some sort of rebound effect occurs in response to thalidomide. Alternatively, thalidomide's primary anti-inflammatory property, the key to its effectiveness, may not really be related to TNFa.

Another surprise in this trial was how poorly tolerated was the 200 mg per day dose. Seventeen of the 31 people receiving the 200 mg dose dropped out, most complaining of somnolence or skin rash. Otherwise the results are in line with, though more modest than, two recently published articles: one describing a small six-month trial in Mexico City (Gustavo Reyes-Téran et al., AIDS, December, 1996 10(14):1501-7), which administered 400 mg/day and a three-week, 300 mg/day Thai study in 32 men with HIV, half of whom also had tuberculosis (Jeffrey Klausner et al., Journal of Acquired Immune Deficiency Syndromes, March, 1996; 11(3):247-57). In the Mexican study, no effect of thalidomide on plasma HIV or TNFa was observed, but the Thai study did find reductions in both these values among the study participants who were co-infected with HIV and TB.

Among the Thai volunteers, baseline TNFa plasma levels seemed to correspond with HIV viral load, with the TB infected group tending to have higher levels of each. Other studies have observed that tuberculosis hastens HIV disease progression, and the enhancement of TNFa production may be related to this acceleration.

Celgene has filed a New Drug Application with the FDA for use of thalidomide for treating a type of aggressive leprosy. Based on the latest results concerning weight gain, it plans to do the same for AIDS wasting syndrome. Further investigation is also taking place concerning thalidomide's ability to reduce oral aphthous ulcers and diarrhea, both of which can interfere with food intake and lead to weight loss. Until the drug is on the market, it is available through a compassionate use protocol for those with uncontrollable AIDS-related weight loss. For more information, call Celgene at 800/801-8328.

Of course, thalidomide is notorious for causing birth defects, and distribution of the substance will have to take place within the context of a rigorous education program to prevent its use during pregnancy. A program that could serve as a model is the one involving Hoffmann-La Roche's widely used acne medication Accutane, which also causes severe birth defects. Aside from the literature it distributes, the Accutane program requires a signed consent form and a negative pregnancy test for women starting Accutane. Roche also recommends that doctors obtain a pregnancy test from their female patients before they renew the Accutane prescription each month. Although Accutane is administered for just five months, pregnancies are still known to occur in women taking it, at a rate of 3.4 per 1,000 female patients according to a Roche survey. Eight percent of these pregnancies were carried to term and resulted in live births.

Evaluating Effectiveness

The relative merits of the anti-inflammatory and anabolic approaches to wasting could be tested this fall in a trial proposed by Dr. Schambelan and others. The trial would compare thalidomide to human growth hormone in people with acute opportunistic infections. In addition, the investigators would try to further unravel the two agents' exact mechanism of action (especially thalidomide's). But, as Dr. Schambelan commented, "Let's not forget about the thalidomide-growth hormone combination." As in the Megace plus testosterone trial mentioned above -- or the often proposed combination of anabolic steroids with exercise programs -- combining wasting treatments may be more effective than any single strategy.

One difficulty in combining approaches is that the evaluation of wasting treatments is still in its infancy. Until last summer, the FDA was insisting that the prime standard for approving an effective anti-wasting therapy was proof that it prolonged patients' lives or at least reduced the incidence of opportunistic infections. Even weight gain was not necessarily sufficient for the FDA: We know that losing weight predicts further disease progression and death, but does gaining weight improve survival? Measures such as improved quality of life or physical performance are extremely subjective or inconclusive, although one could argue that a therapy that makes people function better is worthy of approval. The accuracy of methods for measuring body composition also remain controversial, with many fearing that growth hormone and other anabolic agents largely increase intracellular water or blood proteins rather than the protein content of muscle tissue.

In the case of Serostim, the FDA was faced with considerable pressure from AIDS activists and physicians who insisted that indications of increased lean body mass should be sufficient to allow sales of an anti-wasting treatment. The begrudging approval, granted without evidence of a positive effect on survival or disease progression and conflicting data on weight gain and improved functioning, is evidence of the agency's increasing confusion in this therapeutic area. Last year, the researcher in charge of oxandrolone's clinical trials, Rudolfo Ferraresi, M.D., complained, "When we tried to pin down the FDA on what data we should collect, they didn't come up with anything. They just indicated that if we come to them with compelling data, they might approve the drug. They said wait for the public meeting we are going to have to develop a consensus."

That public meeting finally took place on May 22 and 23, at Treatment Issues' press time. Cosponsored by the Federation of American Societies for Experimental Biology, it featured workshops on wasting syndrome in AIDS and other chronic diseases. At the end, small discussions groups focusing on specific diseases were to formulate guidelines for measuring wasting in patients as well as for evaluating wasting therapies during clinical trials. This meeting is a sequel to the two-day NIH conference referred to above that was devoted to reviewing current knowledge on the causes and treatment of AIDS wasting syndrome.

Bill Thorne, who has kept track of AIDS wasting therapies for ACT UP/Golden Gate, summed up his expectations for the FDA meeting by saying "Similar to the exploration of HIV viral load as a tool for clinical trials, the introduction of body composition measurements will lead to faster approval of therapies and a significant modification of treatment for AIDS-related wasting."

TREATMENT BRIEFS

Glaxo's Parsimonious Compassion

1592U89 is a new nucleoside analog from Glaxo Wellcome that promises to be a marked improvement over present analogs such as d4T or 3TC. In early trials, it was shown to reduce HIV viral loads on its own by up to 1.8 logs (98.4%), and in lab tests, it has strong residual potency against mutant, drug-resistant HIV. Because of this exceptional activity, 1592 is very appealing as salvage treatment for people who are not responding to the antiviral drugs currently on the market.

Discussions between Glaxo and community activists have taken place sporadically for over a year concerning some sort of expanded access program to supply such people while 1592 is under development. On April 28, the company announced the impending commencement of a limited compassionate use program. But this program is so restricted that it has touched off a tidal wave of community criticism.

Glaxo's proposal consists of three programs: a pediatric compassionate use for children who have failed one nucleoside analog, a program for people with "severe" AIDS dementia, and a general adult program. Entry to the general adult program would be restricted to people with viral loads over 50,000 and CD4 counts under 100 after having failed at least two nucleoside analogs and one protease inhibitor. The total worldwide availability will have a ceiling of 2,500 people, which by itself has been cause for a considerable outcry: "We will lose another five to six thousand people in the next year who could be saved by 1592," commented Jeff Getty of ACT UP/Golden Gate.

The enrollment criteria generated a whole slew of objections. Requiring adults to fail two nucleoside analogs and one protease inhibitor before receiving 1592 means that there will be little if anything left to combine the new drug with, given the implications of cross-resistance. To ensure adequate viral suppression and durability of treatment effect, people should take 1592 in combination with other drugs still active against the HIV in their bodies. Preferably that combination would include a protease inhibitor, which 1592 cannot replace. At the very least, the requirement to fail a protease inhibitor should be eliminated. (An alternative would be to undertake a joint expanded access program with Glaxo's experimental protease inhibitor 141W94, which lab studies indicate could be active against HIV resistant to the protease inhibitors on the market.)

Glaxo in addition is forcing both adults and children to wait until they have very high viral loads and low CD4 counts before they can receive 1592. Waiting until that point allows irreparable damage to be done as patients' CD4 cells are decimated and HIV replicates to levels that are hard to bring down. It would have been better to define treatment failure as either an upward trend in viral load or stable, but high HIV levels.

A similar concern arises in relation to the dementia program: Why require that dementia be "severe"? Full recovery may no longer be possible at that point.

Glaxo has responded to these objections by saying that the current supply of 1592 is low and that there is a need to collect extra safety and efficacy data before more broadly releasing the drug. To facilitate this data collection, the general adult compassionate use program will take place at "geographically dispersed centers" rather than the usual central mail order operation. This raises the question as to how people in remote areas will obtain the drug. According to a company announcement, instituting a network of separate sites is part of Glaxo's attempt to build within compassionate use an "open label study which allows for collection of safety and efficacy data... in a broad population of people in addition to that which is being collected through our clinical trials."

It is true that testing has been slow, but the supply problems that supposedly held up trials have been resolved. If Glaxo expects to market 1592 in a year, it must now have the capacity to make commercial-size batches of the substance for the traditional 12-month shelf-life test that new drugs go through. It could use that capacity for a true expanded access program, too.

The company does promise to institute a larger expanded access program next winter, but that will be only a few months before Glaxo anticipates receiving FDA approval for 1592. In the meantime, Glaxo's AZT and 3TC have been the best-selling HIV drugs. Although 1592 will steal some of that market , it can be expected to sell exceedingly well, too. The present demand for immediate access can only bolster its future sales. There is little reason for the miserly expedience that would divert compassionate use from an emergency distribution program into a stop-gap trial.

Some Competition for 1592

DMP 266: DMP 266 is Du Pont Merck's experimental nonnucleoside reverse transcriptase inhibitor. In an initial, trial of low-dose DMP 266 (200 mg once a day) plus indinavir, viral loads were 2.5 logs (99.7%) below baseline at 42 weeks, with 80% of the 21 participants below the viral load assay's level of detection (400 HIV RNA copies/ml of plasma). There are a number of DMP 266 trials in progress or about to begin, including several looking at the drug as part of second-line, replacement regimes in people with long experience on other drugs.

In April meetings with the community, Du Pont Merck discussed its tentative plans for expanded access. The company, like Glaxo, is arguing that drug supplies are limited. It is considering initiating a small compassionate use program in the next few months with a larger, but still modest expanded access program to commence next January. The company would like to organize a joint program that would include Glaxo's 1592 or other drugs, so as to create a fresh multidrug combination that would have a reasonable chance of success in people failing on the drugs available at present.

PMPA: Gilead Sciences announced May 7 that it was commencing a small five-week Phase I/II human trial of an oral prodrug form of PMPA (known as bis-POC-PMPA). The placebo-controlled study will evaluate different doses of oral PMPA in volunteers with CD4 counts above 200 and viral loads over 10,000.

PMPA is a nucleoside analog that has been partly activated through the addition of a phosphate group. In an initial human test, intravenous PMPA monotherapy at 3 mg/kg of body weight reduced HIV levels by more than 1.1 log (92%) after a mere eight injections (on day one and days eight through 14). This reduction was sustained for a week after treatment was terminated. The oral form may be more active than the intravenous form because it better penetrates cells, where it is converted to regular PMPA.

d4T/ddI: The final results of a year-long pilot study of this combination in treatment-naive volunteers were released in April. The average viral load reduction after a year was about 1.3 logs (95%), which is noteworthy but somewhat less than earlier interim analyses indicated. Average CD4 count increased from 330 to 450. Participants in the three higher dose trial arms appeared to receive greater benefit than those in the two lower dose arms.

Peripheral neuropathy has been a major concern with this combination since both ddI and d4T can have this effect when used individually. Only two of the 86 trial volunteers suffered serious peripheral neuropathy, but this cohort was a relatively healthy one and only 20% received full dose of both drugs.

Bristol-Myers Squibb, the drugs' manufacturer, is moving on to trials of d4T/ddI/indinavir. Also, it is working on a once daily adult dose schedule for ddI and is creating a specially coated time-release ddI capsule. That capsule would replace the awkward chewable buffer-containing tablets, which must be taken between meals and frequently cause stomach upset. Bristol expects to seek FDA approval of the capsule early next year.

Marijuana's Ups and Downs in California

An April 21 early morning raid by federal narcotics agents netted over 300 marijuana seedlings at Flower Therapy, one of the San Francisco medicinal marijuana distribution centers that serve people with AIDS. Flower Therapy was trying to operate under the umbrella of California Proposition 215, which state voters passed last fall to authorize physicians' prescription of cannabis. The federal agents acted without the knowledge of local authorities and left before any of Flower Therapy's staff arrived for work. Business was not interrupted, and no arrests have been made so far.

A week later, a federal judge in San Francisco extended a temporary retraining order she had issued April 11 in a separate physicians' and patients' lawsuit. The suit seeks to bar the Clinton administration from penalizing doctors who advise their patients on marijuana's medical uses. Under the preliminary injunction issued by Judge Fern Smith, doctors are protected only up to a point. They still may not actively aid their patients in obtaining marijuana.

A bill proposed in the U.S. Senate by Lauch Faircloth (R-NC) provides for revocation of a doctor's right to prescribe controlled substances and prison terms of up to eight years for physicians who recommend marijuana to patients. At the same time, the California legislature is considering a bill to set up a task force that would study ways of supplying the plant to those with a medical need. The bill also would appropriate $6 million to test marijuana's medical applications. This bill recently received the endorsement of the California Medical Association.

The California bill could be helpful to Donald Abrams, M.D., who is director of the Community Consortium, a Bay Area network of HIV/AIDS care providers. He has been trying for the last three years to put together a feasibility study on using marijuana to reverse AIDS-related anorexia and weight loss. Having run up against a stonewall erected by The Drug Enforcement Administration and the National Institute for Drug Abuse, Dr. Abrams is now re-applying for a research grant from the National Institutes of Health. The NIH rejected a similar grant request from the doctor last year.

A Welcome and an Apology

Starting with the last issue, you may have noticed a new person on TI's bylines and masthead. Treatment Issues welcomes Jill Cadman as its new associate editor. Jill formerly was assistant coordinator of GMHC's Health Care Advocacy Department. She brings to this publication considerable practical experience resolving GMHC clients' problems with the healthcare system. That experience will be very useful in realistically appraising medical therapies. Jill also is an assiduous investigator who will further Treatment Issues' critical analysis of HIV/AIDS treatment developments.

You also may have noticed that Treatment Issues has been very late this spring. We are very sorry. TI editor David Gilden has been working two jobs lately -- in addition to his regular duties, he has been acting director of GMHC's Treatment Education and Advocacy Department. His temporary tenure in that position is now over, and with him back on the job full-time and Jill Cadman settling in, TI should resume its normal schedule -- or maybe not. All GMHC is moving next month, and who knows what chaos will ensue.

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